The Genetic Basis of Resistance to Transplantation Tolerance Induced by Costimulation Blockade in NOD Mice: a Dissertation

The NOD mouse is a widely studied model of type 1 diabetes. The loss of self-tolerance leading to autoimmune diabetes in NOD mice involves at least 27 genetic loci. Curing type I diabetes in mice and humans by islet transplantation requires overcoming both allorejection and recurrent autoimmunity. This has been achieved with systemic immunosuppression, but tolerance induction would be preferable. In addition to their genetic defects in self-tolerance, NOD mice resist peripheral transplantation tolerance induced by costimulation blockade using donor-specific transfusion and anti-CDl54 antibody. Failure has been attributed to the underlying autoimmunity, assuming that autoimmunity and resistance to transplantation tolerance have a common basis. Hypothesizing that these two abnormalities might be related, we investigated whether they had a common genetic basis. Diabetes-resistant NOD and C57BL/6 stocks congenic for various reciprocally introduced Idd loci were assessed for their ability to be tolerized. Surprisingly, in NOD congenic mice that are almost completely protected from diabetes, costimulation blockade failed to prolong skin allograft survival. In reciprocal C57BL/6 congenic mice with NOD-derived Idd loci, skin allograft survival was readily prolonged by costimulation blockade. Unexpectedly, we observed that (NOD x C57BL/6)F1 mice, which have no diabetes, nonetheless resist induction of tolerance to skin allografts. Further analyses revealed that the F1 mice shared the dendritic cell maturation defects and abnormal CD4+ T cell responses of the NOD but had lost its defects in macrophage maturation and NK cell activity. Finally, using a genome wide scan approach, we have identified four suggestive markers in the mouse genome that control the survival of skin allografts following DST and anti-CD154 mAb therapy. We suggest that mechanisms controlling autoimmunity and transplantation tolerance in NOD mice are not completely overlapping and are potentially distinct, or that the genetic threshold for normalizing the transplantation tolerance defect is higher than that for preventing autoimmune diabetes. We conclude that resistance to allograft tolerance induction in the NOD mouse is not a direct consequence of overt autoimmunity and that autoimmunity and resistance to costimulation blockade-induced transplantation tolerance phenotypes in NOD mice are not under identical genetic control

Further explorations of Skyrme-Hartree-Fock-Bogoliubov mass formulas. IX: Constraint of pairing force to 1S0^1S_0 neutron-matter gap

In this latest of our series of Skyrme-HFB mass models, HFB-16, we introduce the new feature of requiring that the contact pairing force reproduce at each density the $^1S_0$ pairing gap of neutron matter as determined in microscopic calculations with realistic nucleon-nucleon forces. We retain the earlier constraints on the Skyrme force of reproducing the energy-density curve of neutron matter, and of having an isoscalar effective mass of $0.8M$ in symmetric infinite nuclear matter at the saturation density; we also keep the recently adopted device of dropping Coulomb exchange. Furthermore, the correction term for the spurious energy of collective motion has a form that is known to favour fission barriers that are in good agreement with experiment. Despite the extra constraints on the effective force, we have achieved a better fit to the mass data than any other mean field model, the rms error on the 2149 measured masses of nuclei with $N$ and $Z \ge$ 8 having been reduced to 0.632 MeV; the improvement is particularly striking for the most neutron-rich nuclei. Moreover, it turns out that even with no flexibility at all remaining for the pairing force, the spectral pairing gaps that we find suggest that level densities in good agreement with experiment should be obtained. This new force is thus particularly well-suited for astrophysical applications, such as stellar nucleosynthesis and neutron-star crusts.Comment: 38 pages, 9 figures accepted for publication in Nuclear Physics

Interaction of Alu Polymorphisms and Novel Measures of Discrimination in Association with Blood Pressure in African Americans Living in Tallahassee

African Americans are 40% more likely to be afflicted with hypertension in comparison to non-Hispanic, white Americans, resulting in a 30% higher instance of mortality due to cardiovascular disease. There is debate about the relative contributions of genetic and sociocultural risk factors to the racial disparity in hypertension. We assayed three Alu insertion polymorphisms located in the angiotensin-1-converting enzyme (ACE), tissue plasminogen activator (PLAT), and with no-lysine kinase 1 (WNK1) genes. We also estimated West African genetic ancestry and developed novel measures of perceived discrimination to create a biocultural model of blood pressure among African- American adults in Tallahassee, FL (n=158). When tested separately, the ACE Alu non-insertion allele was significantly associated with higher systolic and diastolic blood pressure. In multiple regression analyses, West African genetic ancestry was not associated with blood pressure and reduced the strength of all blood pressure models tested. A gene x environment interaction was identified between the ACE Alu genotype and a new measure of unfair treatment that includes experiences by individuals close to the study participant. Inclusion of the WNK1 Alu genotype further improved this model of blood pressure variation. Our results suggest an association of the ACE and WNK1 genotypes with blood pressure that is consistent with their proposed gene functions. Perceived unfair treatment (to others) shows a threshold effect where an increase in blood pressure is demonstrated at higher values. The interaction between the ACE genotype and unfair treatment highlights the benefits of including both genetic and cultural data to investigate complex disease

High-Performance Solid-State W-Band Power Amplifiers

The figure shows one of four solid-state power amplifiers, each capable of generating an output power greater than or equal to 240 mW over one of four overlapping frequency bands from 71 to 106 GHz. (The bands are 71 to 84, 80 to 92, 88 to 99, and 89 to 106 GHz.) The amplifiers are designed for optimum performance at a temperature of 130 K. These amplifiers were developed specifically for incorporation into frequency-multiplier chains in local oscillators in a low-noise, far-infrared receiving instrument to be launched into outer space to make astrophysical observations. The designs of these amplifiers may also be of interest to designers and manufacturers of terrestrial W-band communication and radar systems. Each amplifier includes a set of six high-electron-mobility transistor (HEMT) GaAs monolithic microwave integrated-circuit (MMIC) chips, microstrip cavities, and other components packaged in a housing made from A-40 silicon-aluminum alloy. This alloy was chosen because, for the original intended spacecraft application, it offers an acceptable compromise among the partially competing requirements for high thermal conductivity, low mass, and low thermal expansion. Problems that were solved in designing the amplifiers included designing connectors and packages to fit the available space; designing microstrip signal-power splitters and combiners; matching of impedances across the frequency bands; matching of the electrical characteristics of those chips installed in parallel power-combining arms; control and levelling of output power across the bands; and designing the MMICs, microstrips, and microstrip cavities to suppress tendencies toward oscillation in several modes, both inside and outside the desired frequency bands

Design of HIV-1-PR inhibitors which do not create resistance: blocking the folding of single monomers

One of the main problems of drug design is that of optimizing the drug--target interaction. In the case in which the target is a viral protein displaying a high mutation rate, a second problem arises, namely the eventual development of resistance. We wish to suggest a scheme for the design of non--conventional drugs which do not face any of these problems and apply it to the case of HIV--1 protease. It is based on the knowledge that the folding of single--domain proteins, like e.g. each of the monomers forming the HIV--1--PR homodimer, is controlled by local elementary structures (LES), stabilized by local contacts among hydrophobic, strongly interacting and highly conserved amino acids which play a central role in the folding process. Because LES have evolved over myriads of generations to recognize and strongly interact with each other so as to make the protein fold fast as well as to avoid aggregation with other proteins, highly specific (and thus little toxic) as well as effective folding--inhibitor drugs suggest themselves: short peptides (or eventually their mimetic molecules), displaying the same amino acid sequence of that of LES (p--LES). Aside from being specific and efficient, these inhibitors are expected not to induce resistance: in fact, mutations which successfully avoid their action imply the destabilization of one or more LES and thus should lead to protein denaturation. Making use of Monte Carlo simulations within the framework of a simple although not oversimplified model, which is able to reproduce the main thermodynamic as well as dynamic properties of monoglobular proteins, we first identify the LES of the HIV--1--PR and then show that the corresponding p--LES peptides act as effective inhibitors of the folding of the protease which do not create resistance

Elevated Lipid Oxidation Is Associated with Exceeding Gestational Weight Gain Recommendations and Increased Neonatal Anthropometrics: A Cross-Sectional Analysis

BACKGROUND: Deviations from gestational weight gain (GWG) recommendations are associated with unfavorable maternal and neonatal outcomes. There is a need to understand how maternal substrate metabolism, independent of weight status, may contribute to GWG and neonatal outcomes. The purpose of this study was to explore the potential link between maternal lipid oxidation rate, GWG, and neonatal anthropometric outcomes. METHODS: Women (N = 32) with a lean pre-pregnancy BMI were recruited during late pregnancy and substrate metabolism was assessed using indirect calorimetry, before and after consumption of a high-fat meal. GWG was categorized as follows: inadequate, adequate, or excess. Shortly after delivery (within 48 h), neonatal anthropometrics were obtained. RESULTS: Using ANOVA, we found that fasting maternal lipid oxidation rate (grams/minute) was higher (p = 0.003) among women with excess GWG (0.1019 ± 0.0416) compared to women without excess GWG (inadequate = 0.0586 ± 0.0273, adequate = 0.0569 ± 0.0238). Findings were similar when lipid oxidation was assessed post-meal and also when expressed relative to kilograms of fat free mass. Absolute GWG was positively correlated to absolute lipid oxidation expressed in grams/minute at baseline (r = 0.507, p = 0.003), 2 h post-meal (r = 0.531, p = 0.002), and 4 h post-meal (r = 0.546, p = 0.001). Fasting and post-meal lipid oxidation (grams/minute) were positively correlated to neonatal birthweight (fasting r = 0.426, p = 0.015; 2-hour r = 0.393, p = 0.026; 4-hour r = 0.540, p = 0.001) and also to neonatal absolute fat mass (fasting r = 0.493, p = 0.004; 2-hour r = 0.450, p = 0.010; 4-hour r = 0.552, p = 0.001). CONCLUSIONS: A better understanding of the metabolic profile of women during pregnancy may be critical in truly understanding a woman\u27s risk of GWG outside the recommendations. GWG counseling during prenatal care may need to be tailored to women based not just on their weight status, but other metabolic characteristics